PROJECT SUMMARY By some estimates, up to one million Americans undergo invasive mechanical ventilation (MV) each year. MV can be life-saving, but can also be harmful by leading directly to lung injury by delivering artificially large breaths. A growing body of evidence has demonstrated that a specific strategy of ?lung-protective ventilation? (LPV), which entails smaller breaths and reduced airway pressures, can reduce both short-term mortality and long-term morbidity. Among patients with acute respiratory distress syndrome (ARDS), a form of severe respiratory failure associated with common illnesses such as pneumonia, sepsis, and trauma, high-quality evidence has demonstrated that LPV reduces mortality, duration of mechanical ventilation, and long-term morbidity of patients with ARDS. Nonetheless, many patients with ARDS who undergo mechanical ventilation do not receive this life-saving therapy. Two reasons for this poor evidence uptake are lack of knowledge about LPV and uncertainty regarding who has ARDS at the time of MV initiation. However, recent recognition that LPV may improve outcomes even among patients without ARDS suggests that encouraging clinicians to begin with LPV for all patients may be an optimal strategy. Therefore, our main objective is to study simple strategies that may circumvent the barriers of knowledge and diagnostic uncertainty, to improve the utilization of LPV. We will conduct a large pragmatic trial of electronic health record (EHR)-based implementation strategies informed by behavioral economic principles to encourage LPV utilization among all MV patients. We will employ a Hybrid Trial Type 3 design to study implementation and effectiveness outcomes. We will test two hypotheses: (1) that a default order set (pre-populated with LPV settings) or an accountable justification prompt (requiring physicians to provide an explicit rationale when non-LPV settings are ordered) will increase LPV utilization among patients with and without ARDS, will be sustainable, and will improve overall clinical outcomes; and (2) that the addition of an accountable justification prompt requiring respiratory therapists to provide a rationale when non-LPV settings are documented will further improve outcomes. We will use a stepped-wedge, cluster randomized design across 12 ICUs. The specific aims of this trial are to: (1) compare fidelity to LPV with the implementation strategies; (2) evaluate the sustainability of the strategies and their effects; (3) explore whether clinician and environmental contextual factors modify the effect of the strategies; (4) compare the effectiveness of strategies to improve patient outcomes; (5) compare the specific efficacy of these strategies, accounting for imperfect adherence to LPV; and (6) evaluate how patient heterogeneity interacts with the strategies. This study will provide high-quality evidence regarding the ability of simple, readily scalable interventions to improve evidence-based practices among patients with very high morbidity and mortality, will expand the literature on effectiveness of LPV among broader patient populations, and will improve understanding of the utility of different behavioral economic strategies in settings in which treatment effects may be heterogeneous.